Gender differences in pain and analgesia produced from opioid analgesics have been well documented in both animal and human clinical studies. Many of these studies have characterized factors that contribute to gender-specific pharmacodynamic differences in response to painful stimuli and alteration of the response with opioid analgesics. However pharmacokinetic factors, which may also contribute to this difference, have not been studied to the same detail. There are many reports identifying endogenous and exogenous compounds that interact with morphine by altering its metabolism, but understanding the resulting impact on analgesia is complicated by temporal delays in the pharmacokinetic effects. Using a computer-controlled, pharmacokinetically driven infusion of morphine, we have developed a study method for assessing the interaction of a parent drug with its active metabolites that takes advantage of the temporal lag that occurs in metabolite formation. In this exploratory R21 proposal, we will use pharmacokinetics to fix the concentration of one agonist agent, morphine, so that the impact of its active and inactive metabolites, whose concentrations we cannot control, can be rationally assessed. By conducting these studies in subjects where gonadal steroid hormones are held stable by oral contraceptives and in subjects where they cyclically fluctuate, we will begin to discern the difference between the pharmacokinetic and pharmacodynamic influences that gonadal steroid hormones have on analgesia produced by morphine. The results of this project will determine gender differences and important pharmacokinetic and pharmacodynamic covariates to aid in appropriate dosing strategies for the most widely prescribed opioid analgesic. [unreadable] [unreadable]